Principal Investigator/Program Director (Last, First, Middle): Stewart, Paul W. Abstract Owing to a legacy of industrial pollution throughout the 20th Century, children in the Great Lakes region in the United States are exposed to mixtures of environmental contaminants; some of the most significant contaminants are polychlorinated biphenyls (PCBS) and methylmercury (MeHg). It is important to underscore that these exposures occur in children who are already exposed to background levels of well-understood contaminants, such as lead (Pb). Each of these contaminants is potentially neurotoxic, and, in fact, all have been implicated in neurobehavioral deficits in children. Families in the Great Lakes region are particularly at risk for exposure. Multiple exposure pathways include dietary intake of Great Lakes sport fish, the legacy of industrial, agricultural and landfill waste and downwind pollution from energy production facilities. The fact that our study population has likely experienced these exposure routes allows us to examine the impact of both individual and combined exposure to these contaminants through the middle teenage years. This goal is informed recent data by which show that prenatal PCB exposure predicts impulsive behavior and impaired inhibitory control from ages 4 [unreadable] years through 13 years of age. The Oswego Project has repeatedly demonstrated that PCB exposure is related to an impaired ability to inhibit behavior, or impaired response inhibition. During the last granting period, the data on this phenomenon has advanced to the point where the Project can confirm that this deficit is characterized by an inability to inhibit prepotent response tendencies, rather than just excessive motor activity, perseveration, or an attentional deficit. While these findings have advanced the field in important ways, it is the data that relate to the putative effects of PCBs, in combination with MeHg, and even Pb, that is most compelling and hold the most promise for the current proposal. As the behavioral significance of PCB exposure continues to be clarified and linked to inhibition and response control, effects of both MeHg and Pb have begun to emerge on these endpoints. The goal of the current proposal is to use the knowledge we have obtained to test new and important hypotheses regarding the mixture of these toxics on behavior. In doing so, we may reveal that both the effects of individual contaminants and the cumulative impact of combined exposures may result in clinically significant impairments. Within the scope of these parameters, we believe that the design and methodology of the proposed project is ideally suited to examine the important putative effects of PCB, MeHg and Pb on response inhibition. PHS 98/50 Rv. 09/4, Reissued 4/2006) Pg Continuation Format Page Relevance There is reasonable evidence from research studies that indicate that prenatal exposure to PCBs produces impairments in cognitive development in children. The Oswego Project represents one of the few major, longitudinal studies in the United States designed to assess the effects of exposure to low levels of PCBs on child development. The stable nature of the cohort, the 14 years of experience the Principal Investigators have with these cohorts, the well-established testing protocols, and the extensive database of exposure, outcome and potentially confounding/ mediating variables permit rigorous assessment of the impact of prenatal PCB exposure in the early teen years.